Site specific delivery of co-administered drugs via inhalation

ABSTRACT

Two or more drugs of different particle size are packaged for co-administration to the respiratory pathway.

The present invention relates to the packaging of and co-administrationof pharmaceuticals and drugs for medical uses. The invention hasparticular utility in packaging and administration of precise amounts oftwo or more pharmaceuticals and drugs to different sites in therespiratory and/or respiratory alimentary pathway, and will be describedin connection with such utility, although other utilities arecontemplated.

There is a growing trend in the pharmaceutical industry to combinemultiple therapeutic medications for the improved treatment of manychronic diseases Examples of this trend are represented in the areas ofdiabetes and, respiratory and allergy (asthma, COPD) treatment, etc.Specific examples are described below.

New research has demonstrated that the combination of leukotrienereceptor antagonists (LTs) with corticosteroids can improve efficacy forasthmatics and with improved safety. LTs are alternatives to long-actingbeta-agonists as complementary treatment to inhaled corticosteroids inboth pediatric and adult asthma management because they providebronchodilation and bronchoprotection without development of tolerance,and complement the anti-inflammatory activity unchecked by steroids.

As a result of the above findings, LTs and steroids are currently beingco-prescribed with good effect in asthmatics today. The currenttreatment regimen calls for the patient to take the LT in an oral dose(pill), while the steroid is inhaled using an inhaler. There iscurrently no product available that delivers these two products incombination. Examples of two LTs on the market are: Merck's Singulair®,chemical name Montelukast, and AstraZeneca's Accolate®, chemical nameZafirlukast. Two highly prescribed corticosteroids on the market areGlaxoSmithKline's Flovent®, chemical name Fluticasone, and AstraZeneca'sPulmicort®, chemical name Budesonide.

The current regimen for the treatment of diabetes as the diseaseprogresses is to use combination therapy to control the blood glucoselevel in patients. A common practice is to combine an oral dosagemedication with injectable insulin. Companies such as GlaxoSmithKlineand Eli Lilly have received regulatory approval to market theirglitazone products in combination with insulin. These glitazones arecurrently administered in solid oral dosage forms. There is alsoconsiderable work currently underway by companies such asPfizer-Aventis-Nektar, Novo Nordisk-Aradigm, Eli Lilly-Alkermes,MicroDose Technologies, etc to deliver insulin to the lungs via theinhalation route to treat diabetes.

We believe that by combining the two separate modes of delivery, oraland inhalation, into one mode of delivery i.e. inhalation, will resultin higher compliance and therefore improved efficacy.

The present invention provides a medication delivery system in which twoor more pharmaceuticals or drugs are delivered to different sites in therespiratory pathway. More particularly, in accordance with the presentinvention, the particle size of different drugs is controlled accordingto aerodynamic particle size principles so as to determine the site ofaction or absorption of the drug in the respiratory pathway. As aresult, it is possible to co-administer, simultaneously, by inhalation,two or more different drugs for absorption or depositing in either themouth or throat where the drug will be dissolved and absorbed in thealimentary canal, and also deliver drugs to the lungs of where the drugswill be absorbed in the respiratory pathway.

As used herein, the term respiratory pathway shall include both therespiratory and alimentary pathways, and shall encompass the nasal andmouth openings, the throat and the lungs.

Further features and advantages of the present invention will be seenfrom the following detailed description, taken in conjunction with theaccompanying drawing, wherein:

FIG. 1, which is a diagrammatical drawing showing powder dispersion andhow it relates to human anatomy.

FIG. 2 is a side elevational view of an apparatus made according to thepresent invention; and

FIG. 3 is a top plan view of a cartridge tape made in accordance with apreferred embodiment of the instant application.

In overview, the present invention is based on the realization thatinhaled particles can be delivered to different sites in the respiratorypathway depending upon their aerodynamic particle size. This leads tothe ability to direct or control the specific site delivery ofpharmaceuticals from an inhaler by tailoring particle sizes. By way ofexample, and in reference to FIG. 1, dry powder delivered from aninhaler and having a particle size greater than about 9 microns,typically will be deposited in either the mouth or throat where it willdissolve and enter a patient's body through the alimentary canal, andwhereas drugs have a particle size less than about 5.8 microns inmaximum size will be delivered to the lungs. As seen in FIG. 1, thesmaller particle size, the deeper into the lungs will be the delivery.

The present invention provides for co-administration of drug productseither simultaneously, sequentially or separately by inhalation. Thedrugs are delivered to their respective target sites of action, i.e. inthe mouth, throat or lungs, through manipulation of the drug particlesize. In various embodiments of the invention, the drugs are deliveredeither from the same drug container simultaneously, i.e. via the sameinhalation or puff; simultaneously from separate drug containers; orsequentially from the same or separate drug containers, either in asingle inhalation or puff or multiple inhalations or puffs.

In a preferred embodiment of the invention, two or more drugs aredelivered simultaneously, i.e. in a single inhalation, using aninhalation device as described in prior U.S. Pat. No. 6,026,809 assignedto the common assignee, but modified to deliver two or more drugssimultaneously. In other words, and with reference to FIG. 2, whichcorresponds to FIG. 9 of U.S. Pat. No. 6,026,809, the disposable drugcartridge 210 comprises an outer housing 212 which includes a tab 214for slidably mounting in a recess 216 formed integrally with housing202. Drug cartridge 210 includes a coiled tape 218 carrying a pluralityof spaced bubbles or wells 220 for carrying a dry powder medicament. Arelease film 221 covers and seals wells 220. Tape 218 is formed as acoil, and is threaded between a first guide platen 222 and pinch roller224. Pinch roller 224 in turn is driven by a take-up spool 226, which inturn is driven by a thumbwheel 228, which is mounted, on a common shaftwith the take-up spool 226. In use, release film 221 is peeled from thetape 218, whereby to expose wells 220, one at a time, as the film isadvanced through the cartridge, and the release film 221 is collected ontake-up spool 226.

Completing cartridge 210 is a piezoelectric element 232 for mechanicallyengaging wells 220, as they are selectively advanced in position overand in contact with the piezoelectric element 232. Tape 218 alsopreferably includes detent means or the like for indexing the tape sothat a selected well 220 is automatically positioned over piezoelectricelement 232. Finally, an actuating circuit and power supply, similar tothat previously discussed, is mounted within cartridge 210.

In one embodiment of the invention, two or more pharmaceuticals or drugshaving the same or different particle size may be blended together andloaded in the individual wells 220 for co-delivery. Alternatively, andpreferably, as shown in FIG. 3, different pharmaceuticals or drugshaving the same or different particle sizes are carried in separatewells 220A, 220B positioned adjacent one another on tape 218 so that thetwo different pharmaceuticals or drugs may be simultaneously deliveredin a single inhalation or puff. Packaging of the differentpharmaceuticals or drugs in separate wells 220A, 220B also has theadvantage of avoiding possible adverse chemical reaction between the twopharmaceuticals or drugs, reduced formulation demands in terms ofhomogeneity and settling in blending of the drugs, improved accuracy infilling of the individual drugs into the separate wells and a higherconsistency in dose-to-dose repeatability in delivering the drugs.

In another embodiment, the different pharmaceuticals or drugs are loadedin alternate wells 220 along tape 218 whereupon the differentpharmaceuticals or drugs may be sequentially administered, i.e. inmultiple inhalations.

Summarizing to this point, in accordance with the present invention,particle size of drugs to be administered by inhalation are controlledin order to tailor the delivery of the drug to a selected site in therespiratory pathway or alimentary canal depending on the drug'saerodynamic particle size. This permits selective delivery optionsincluding:

-   -   1. Buccal delivery—wherein a drug primarily is deposited on        buccal mucosa, and the drug has local effect, or absorption        takes place through buccal mucosa for systemic effect;    -   2. Oral delivery—wherein a drug primarily is deposited in the        mouth, or throat, and is then swallowed to stomach where it has        local effect or is absorbed for systemic effect;    -   3. Intra-nasal delivery—wherein a drug primarily is deposited in        the nasal passages, and has local effect, or is absorbed through        the nasal mucosa for systemic effect; and    -   4. Pulmonary delivery—wherein a drug primarily is deposited on        the lungs, and has local effect, or is absorbed through lungs        for systemic effect.

The co-administration of separate drug products for inhalation deliveryin accordance with the present invention can be grouped intopolypharmacy for treatment of a single condition, into polypharmacy fortreatment of co-morbid conditions, and for co-administration of separatedrug products wherein one drug product is administered to manage sideeffects resulting from administration of the other drug product. Theinvention will now be described with reference to the followingnon-limiting examples:

Combination I A Broncodilator and an Anti-Inflammatory

An Anti-Leukotriene antagonist such as montelukast¹ of particle sizeabout 9 microns for delivery to the mouth for absorption in thealimentary canal, and Budesonide² particles having a particle size ofless than about 6 microns for delivery to the lungs.¹ Montelukast::[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneaceticacid, monosodium salt.² Budesonide:(RS)-11β,16α,17,21-Tetrahydroxypregna-1,-4-diene-3,20-dione cyclic16,17-acetal with butyraldehyde.

Combination II Broncodilator and Anti-Inflammatory for Asthma

Budesonide particles as described in Combination I, plus Zafirlukast³ ofparticle size greater than about 9 microns for delivery to the mouth forabsorption in the alimentary canal.³ Zafirlukast:4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-n-0-tolylsulfonylbenzamide.

Combination III Oral Agents plus Insulin for Diabetes Management

Insulin of particle size less than about 3 microns for delivery to thelungs, plus a sulfonylurea such as glipizide⁴ of particle size greaterthan about 9 microns for delivery to the mouth for absorption in thealimentary canal.⁴ Glipizide:1-cyclo-hexyl-3-[[p-[2(5-methylpyrazinecarboxamido)-ethyl]-phenyl]sulfonyl]urea.

Combination IV Oral Agent Plus Insulin

Insulin as in Combination III, plus a Thiazolidinedione such asRosiglitazone maleate⁵ having a particle size greater than 9 microns fordelivery to the mouth for absorption in the alimentary canal.⁵ Rosiglitazone maleate:(+)-5[[4-[2-(methyl-2-pyridinylamino)ethoxyl]phenyl]methyl]-2,4-thiazolidinedi-one,(Z)-2-butenedioate (1:1).

Combination V Oral Agent Plus Insulin

Insulin as in Combination III, plus Acarbose⁶ having a particle sizegreater than 9 microns for delivery to the mouth for absorption in thealimentary canal.⁶ Acarbose:O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclo-hexen-1-yl]amino]-a-D-glucopyranosyl-(14)-O-a-D-glu-copyranosyl-(1 4)-D-glucose.

Combination VI

Insulin as in Combination No. III and a Viguanide such as Metformin⁷having a particle size greater than 9 microns for delivery to the mouthfor absorption in the alimentary canal.⁷ Metformin: (N,N-dimethylinidodicarbonim-idic diamide hydrochloride).

The following Examples VI and VIII illustrate the co-administration ofseparate drug products for co-morbid conditions with a high rate ofclinic co-occurrence.

Combination VII

Eighty percent (80%) plus of diabetics are also hypertensive. Therefore,a combination of insulin having a particle size of less than about 3microns and a drug for controlling hypertension such as Losartan⁸ of aparticle size greater than 9 microns for delivery to the mouth forabsorption in the alimentary canal.⁸ Losartan:2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)-benzyl]imidazole-5-methanolmonopotassium salt.

Combination VIII

Insulin of particle size less than about 6 microns for delivery to thelungs, in combination with an ACE Inhibitor such as Lisinopril⁹ ofparticle size greater than about 9 microns for delivery to the mouth forabsorption in the alimentary canal.⁹ Lisinopril: (S)-1-[N²-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-prolinedihydrate.

The following example IX illustrates a combination drug delivery systemof the present invention for co-administration of separate drug productswhere one product is given to manage side-effects (acute or chronic)resulting from the administration of the other drug product.

Combination IX

Cancer therapies, which include, but are not limited to cytotoxins,often have the side effect of nausea and vomiting. Thus, a combinationof a lung cancer therapeutic of particle size less than 6 microns forlocal or systemic treatment to the lungs, and an anti-emetic of aparticle size of greater than 9 microns to delivery to the mouthadvantageously may be provided.

It should be noted that other drug combinations might be packaged anddelivered in accordance with the present invention without departingfrom the spirit and scope thereof.

1. A method for delivering drugs via a patient's respiratory pathwaywhich comprises delivering two or more drugs, of different particlesize, to different sites in the respiratory pathway.
 2. A methodaccording to claim 1, wherein at least one of the drugs is deposited inthe mouth or throat for delivery to the alimentary canal.
 3. Accordingto claim 1, wherein at least one of the drugs is delivered to the lungs.4. A method according to claim 2, wherein the drug is delivered to thealimentary canal have a particle size greater than about 9 microns.
 5. Amethod according to claim 3, wherein the particles delivered to thelungs have a particle size less than about 5.8 microns.
 6. A methodaccording to claim 1, wherein the two or more drugs are deliveredsimultaneously.
 7. A method according to claim 1, wherein the two ormore drugs are delivered sequentially.
 8. An inhalation device fordelivering drugs to a patient, wherein the drugs comprise two or moredrugs having different particle sizes.
 9. An inhalation device asclaimed in claim 8, wherein at least one of said drugs has a particlesize greater than about 9 microns.
 10. An inhalation device as claimedin claim 8, wherein at least one of said drugs has a particle size lessthan about 5.8 microns.
 11. An inhalation device as claimed in claim 8,wherein said two or more drugs are packaged together.
 12. An inhalationdevice as claimed in claim 8, wherein said two or more drugs arepackaged separately.
 13. A method for delivering drugs via a patient'srespiratory pathway which comprises delivering two or more drugs ofdifferent particle sizes, to different sites in the respiratory pathwaywhere the drugs are from a group of respiratory therapeutic agents. 14.A method according to claim 13 wherein one of the agents is ananti-luketriene antagonist.
 15. A method according to claim 13 whereinone of the agents is a cortico-steroid.
 16. A method for deliveringdrugs via a patient's respiratory pathway which comprises delivering twoor more drugs of different particle sizes, to different sites in therespiratory pathway where the drugs are from a group of diabetic controlagents.
 17. A method according to claim 16 wherein one of the drugs isinsulin.
 18. A method according to claim 16 wherein one of the drugs isan oral agent such as glipizide and/or thiazolidinedione and/or acarboseand/or viguanide.
 19. A method for delivering drugs via a patient'srespiratory pathway which comprises delivering two or more drugs ofdifferent particle sizes, to different sites in the respiratory pathwaywhere the drugs represent a combination of drugs to treat the co-morbidcondition of diabetes and/or hyperlipidemia and/or hypertension.
 20. Amethod according to claim 19 wherein one of the drugs comprises astatin.
 21. A method according to claim 20 wherein one of the statinscomprises Lovastatin or Simvastatin.
 22. A method according to claim 19wherein one of the drugs is selected from the group consisting of one ormore of an ACE inhibitor, a calcium channel blocker, and an ARB.
 23. Amethod for delivering drugs via a patient's respiratory pathway whichcomprises delivering two or more drugs of different particle sizes, todifferent sites in the respiratory pathway where one of the drugs isgiven to treat or manage the side effects of the other drug.
 24. Aninhalation device for delivering drugs to a patient, wherein the drugscomprise two or more drugs having different particle sizes and where thedrugs are from a group of respiratory therapeutic agents.
 25. A methodaccording to claim 24 wherein one of the agents is an anti-luketrieneantagonist.
 26. A method according to claim 24 wherein one of the agentsis a cortico-steroid.
 27. An inhalation device for delivering drugs to apatient, wherein the drugs comprise two or more drugs having differentparticle sizes and where the drugs are from a group of diabetic controlagents.
 28. A method according to claim 27 wherein one of the drugs isinsulin.
 29. A method according to claim 27 wherein one of the drugs isselected from the group consisting of one or more of glipizide,thiazolidinedione, acarbose and viguanide.
 30. An inhalation device fordelivering drugs to a patient, wherein the drugs comprise two or moredrugs having different particle sizes and where the drugs represent acombination of drugs to treat the co-morbid of diabetes and/orhyperlipidimia and/or hypertension.
 31. A method according to claim 30wherein one of the drugs comprises a statin.
 32. A method according toclaim 31, wherein one of the statins comprises Lovastatin orSimvastatin.
 33. A method according to claim 30 wherein one of the drugsis selected from the group consisting of one or more of an ACEinhibitor, a calcium channel blocker, and an ARB.
 34. An inhalationdevice for delivering drugs to a patient, wherein the drugs comprise twoor more drugs having different particle sizes and where one of the drugsis given to treat or manage the side effects of the other drug.